Selective serotonin reuptake inhibitors (SSRIs) are a class of medication used primarily to treat psychiatric disorders, including depression, obsessive-compulsive syndromes, and others. These agents are believed to exert their therapeutic action by blocking neuronal uptake of serotonin, thereby resulting in increased levels of serotonin. Because of this mechanism of action, SSRIs often regarded as treating the symptoms of depression more effectively than other commonly prescribed antidepressant agents such as tricyclic antidepressant agents. In addition, some metabolic disorders that are affected by serotonin levels have benefited from the use of SSRIs. The most common SSRIs include fluoxetine (Prozac®), sertraline (Zoloft®), paroxetine (Paxil®), fluvoxamine (Luvox®), and citalopram (Celexa®).
A preferred SSRI is fluoxetine, which chemically is dl-N-methyl-γ-[4-(trifluoromethyl)phenoxy]benzenepropanamine. Fluoxetine is chemically unrelated to the tricyclic, tetracyclic, or other available antidepressant agents. It has an empirical formula of C17H18F3NO.HCl, a molecular weight of 345.79 and is commonly utilized as the hydrochloride salt. Fluoxetine is a selective serotonin uptake inhibitor useful in the treatment of depression, anxiety, bulimia, obesity, obsessive compulsive syndrome and other disorders including migraine and pre-menstrual dysphoric disorder (PMDD).The antidepressant, anti-obsessive-compulsive, and anti-bulemic actions of fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. The most commonly observed adverse events associated with the use of fluoxetine are nausea, headache, insomnia, anxiety, nervousness, somnolence, and sexual dysfunction.
Traditionally, fluoxetine and other SSRIs have been administered orally in the form of tablets, capsules, granules, and pills. Fluoxetine oral dosages range from about 20 mg to 80 mg daily depending on the individual patient and the disorder being treated. Such oral administration inherently subjects the active agent to a first pass metabolism in the liver before permitting the SSRIs to circulate throughout the body. The half life of fluoxetine (2–3 days) and its active metabolite norfluoxetine (7–9 days) is relatively long. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. The complexity of the metabolism of fluoxetine combined with the variability in metabolism of the drug among individuals has several clinical consequences. Accordingly, there is a need for a delivery method that is less dependent on metabolic variability from patient to patient, and allows for greater control over circulating levels of active agents and metabolites.
Vaginal dosage forms are known for the local administration of medicaments for the treatment of gynecological and obstetric conditions. The principal advantage of such dosage forms is that small doses of medicament can be administered locally, which is preferable to systemic treatment of the same conditions which typically requires larger doses to affect the same results. However, it is neither taught nor suggested in the literature that medicaments, such as SSRIs, could be administered via the intravaginal or rectal routes for delivery into the systemic circulation. It has been unexpectedly discovered, and thus forms the basis of the present invention, that the problems of metabolic variability with selected serotonin reuptake inhibitors alluded to above can be substantially resolved by administration via the intravaginal or rectal routes.